Shi Pengzhi, Gao Haiyang, Cheng Zhangrong, Wu Wenbo, Zhang Anran, Chen Xianglong, Wu Wang, Zhang Yukun
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Extracell Vesicles. 2025 Aug;14(8):e70148. doi: 10.1002/jev2.70148.
Mesenchymal stem cell (MSC) transplantation is considered one of the most promising regenerative strategies for treating degenerative musculoskeletal diseases, yet its underlying therapeutic mechanisms remain incompletely understood. In this study, we demonstrate that transplanted MSCs regulate apoptosis and DNA damage repair (DDR) in senescent nucleus pulposus cells (NPCs) by releasing apoptotic extracellular vesicles (ApoEVs), thereby delaying the process of intervertebral disc degeneration (IVDD). Mechanistically, we found that NPCs in degenerated discs exhibit abnormal subcellular localization of the deubiquitinase ubiquitin specific peptidase 5 (USP5), with excessive cytoplasmic retention leading to aberrant ubiquitination and degradation of the E2F transcription factor 1 (E2F1). Following transplantation into the degenerative disc microenvironment, MSCs undergo extensive apoptosis in the short-term and release ApoEVs enriched in highly acetylated USP5. These vesicles promote nuclear translocation of USP5 in NPCs, which stabilizes E2F1 by preventing its ubiquitin-mediated degradation. This cascade reduces DNA damage and apoptosis in NPCs and enhances their functional activity. Overall, our findings reveal a previously unrecognized mechanism by which apoptotic donor MSCs exert therapeutic effects through intercellular communication, specifically by modulating recipient NPCs apoptosis and DDR pathways. This study underscores the critical role of donor cell apoptosis in the therapeutic efficacy of stem cell transplantation and provides new insights for optimizing regenerative medicine strategies.
间充质干细胞（MSC）移植被认为是治疗退行性肌肉骨骼疾病最有前景的再生策略之一，但其潜在的治疗机制仍未完全明确。在本研究中，我们证明移植的间充质干细胞通过释放凋亡细胞外囊泡（ApoEVs）来调节衰老髓核细胞（NPCs）的凋亡和DNA损伤修复（DDR），从而延缓椎间盘退变（IVDD）进程。机制上，我们发现退变椎间盘中的NPCs表现出去泛素化酶泛素特异性肽酶5（USP5）的异常亚细胞定位，过多的胞质滞留导致E2F转录因子1（E2F1）的异常泛素化和降解。移植到退变椎间盘微环境后，间充质干细胞在短期内经历广泛凋亡并释放富含高度乙酰化USP5的ApoEVs。这些囊泡促进USP5在NPCs中的核转位，通过防止其泛素介导的降解来稳定E2F1。这一连串反应减少了NPCs中的DNA损伤和凋亡，并增强了它们的功能活性。总体而言，我们的研究结果揭示了一种以前未被认识的机制，即凋亡的供体间充质干细胞通过细胞间通讯发挥治疗作用，特别是通过调节受体NPCs的凋亡和DDR途径。本研究强调了供体细胞凋亡在干细胞移植治疗效果中的关键作用，并为优化再生医学策略提供了新的见解。
